Glioma stem cells-derived exosomal miR-26a promotes angiogenesis of microvessel endothelial cells in glioma

J Exp Clin Cancer Res. 2019 May 17;38(1):201. doi: 10.1186/s13046-019-1181-4.

Abstract

Background: Cancer stem cells (CSCs), which are involved in cancer initiation and metastasis, could potentially release exosomes that mediate cellular communication by delivering microRNAs (miRNAs). Based on the role of miR-26a in angiogenesis of glioma, our study was performed to investigate whether glioma stem cells (GSCs)-derived exosomes containing miR-26a could exert effects on angiogenesis of microvessel endothelial cells in glioma, in order to provide a new therapeutic RNA vehicle for glioma therapies.

Methods: The expression of miR-26a and PTEN in glioma was quantified and the interaction among miR-26a, PTEN and PI3K/Akt signaling pathway was examined. Next, a series of gain- and loss-of function experiments were conducted to determine the role of miR-26a in angiogenesis of human brain microvascular endothelial cells (HBMECs). Subsequently, HBMECs were exposed to exosomes derived from GSCs with the gain-/loss-of-function of miR-26a. Finally, the effect of exosomal miR-26a on angiogenesis of HBMECs was assessed both in vitro and in vivo.

Results: The results revealed that PTEN was down-regulated, while miR-26a was up-regulated in glioma. miR-26a activated the PI3K/Akt signaling pathway by targeting PTEN. Restored miR-26a promoted proliferation, migration, tube formation, and angiogenesis of HBMECs in vitro. In addition, GSCs-derived exosomes overexpressing miR-26a contributed to enhanced proliferation and angiogenesis of HBMECs in vitro through inhibition of PTEN. The angiogenic effects of GSCs-derived exosomes overexpressing miR-26a in vivo were consistent with the above-mentioned in vitro findings.

Conclusion: Collectively, our study demonstrates that GSCs-derived exosomal miR-26a promotes angiogenesis of HBMECs, highlighting an angiogenic role of miR-26a via exosomes.

Keywords: Angiogenesis; Exosomes; Glioma stem cells; Microvessel endothelial cells; PI3K/Akt signaling pathway; Phosphatase and tensin homolog deleted on chromosome ten; microRNA-26a.

MeSH terms

  • Adult
  • Aged
  • Animals
  • Cell Movement / genetics
  • Cell Proliferation / genetics*
  • Coculture Techniques
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Exosomes / genetics
  • Exosomes / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Glioma / genetics*
  • Glioma / pathology
  • Heterografts
  • Humans
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Microvessels / metabolism
  • Microvessels / pathology
  • Middle Aged
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Proto-Oncogene Proteins c-akt / genetics
  • Signal Transduction / genetics

Substances

  • MIRN26A microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human